# Krisanaklan Reduces Intestinal Anion and Fluid Secretion Through Inhibition of Na+/K+‐ATPase and K+ Channel Activity

## TL;DR

Krisanaklan reduces intestinal fluid secretion by inhibiting key ion transporters, which may help treat diarrhea but could interfere with rehydration therapy.

## Contribution

Krisanaklan's novel mechanism of inhibiting Na+/K+-ATPase and K+ channels to reduce intestinal secretion is identified.

## Key findings

- Krisanaklan inhibits cAMP-dependent anion and fluid secretion in intestinal epithelia.
- It blocks Na+,K+-ATPase and K+ channels but does not affect apical anion transport.
- Krisanaklan may ameliorate secretory diarrhea but could interfere with oral rehydration therapy.

## Abstract

Krisanaklan (KK) is a traditional herbal remedy used to treat an array of gastrointestinal complaints, including infectious, secretory diarrhea (SD). We assessed the effect of KK on anion and fluid secretion across intestinal epithelia, and delineated its mode of action. KK inhibited cholera toxin/cAMP‐dependent anion secretion across intestinal epithelial monolayers and native intestinal epithelium ex vivo. Similarly, KK reduced cAMP‐dependent fluid secretion in intestinal organoids. KK inhibited Na+,K+‐ATPase (NKA)‐mediated, ouabain‐sensitive ion transport and channel‐mediated K+ efflux across the basolateral plasma membrane but did not block cAMP‐dependent anion transport across the apical plasma membrane. KK also inhibited ouabain‐insensitive ATPase activity, but did not affect cAMP‐dependent protein phosphorylation. KK reduced carrier‐mediated amino acid uptake in Caco‐2 cells and Na+‐coupled glucose transport in porcine intestine. Further, KK inhibited cGMP‐ and Ca2+‐linked anion secretion across intestinal epithelial monolayers. We conclude that KK blocks intestinal epithelial anion and fluid secretion by inhibition of the NKA and K+ channels. Consequently, KK may ameliorate SD caused by enteric microbial pathogens. However, by inhibiting the activity of Na+‐dependent solute carriers, it is also predicted to counteract oral rehydration therapy, the current mainstay for SD therapy.

Krisanaklan reduces CFTR‐dependent intestinal chloride and fluid secretion by inhibiting the Na+,K+‐ATPase and K+ channels in epithelial cells. Consequently, this natural, plant‐derived product may limit secretory diarrhea caused by a diverse array of microbial pathogens. However, by dissipating the transmembrane Na+ gradient, Krisanaklan also inhibits SGLT1‐mediated, Na+‐coupled glucose uptake. Therefore, it must not be used as adjunct to oral rehydration solution (ORS).